Purpose Small bowel obstruction (SBO) usually resolves with medical therapy but requires surgery, preferentially under the guidance of laparoscopy. We performed single-port flexible endoscopic enterolysis for abdominal adhesions under the guidance of dual-channel electromagnetic navigation technology and evaluated the feasibility and safety of this method in a pig model.Method Hypochlorite-induced abdominal adhesions was induced in 8 pigs. A long gastric tube with a magnetic navigation wire (sensor 1) was inserted into the distal end of the small intestine. The electromagnetic signal emitter was activated, and a second magnetic navigation wire (sensor 2) was continuously adjusted on the abdominal surface to obtain the two coordinates closest to the incised skin. The trocar was placed, and pneumoperitoneum was established. An endoscope with a second wire was placed through the trocar, and diagnostic intraperitoneal endoscopy was performed. The fibrotic bands and peritoneal congestion were observed, and the fibrous bands were dissected with a Dual knife.Results Abdominal adhesions model was evaluated. One case experienced intraoperative bleeding because the small mesenteric artery was damaged. Both the peritoneum and operating space were sufficiently visible in all cases except one, in which intestinal inflation significantly affected visibility. Seven of 8 (87.5%) of fibrous bands were successfully dissected. The total procedure duration was 48 (35-60) mins. Compared with that in the hypochlorite-induced abdominal adhesions model, weight gain was 6 (4-9) kg.Conclusion Flexible endoscopy adhesiolysis under the guidance of electromagnetic navigation for abdominal adhesions is comparatively safe and feasible.

Quercetin exhibits potent anti-hepatitis B virus (HBV) activity through a host-directed mechanism involving innate immune activation. In this study, quercetin was evaluated in a panel of in vitro and in vivo HBV infection models, where it effectively suppressed HBV replication and reduced viral antigen expression. Mechanistically, quercetin activated the RIG-I/MAVS signaling pathway, thereby enhancing downstream antiviral signaling and promoting interferon (IFN)-β production. Molecular interaction analysis and RIG-I knockdown experiments further demonstrated that quercetin directly binds to RIG-I and exerts its antiviral effects in a RIG-I-dependent manner. These findings establish the quercetin-induced activation of the RIG-I/MAVS axis as a key mechanism underlying its anti-HBV activity and highlight quercetin as a promising host-targeting candidate for HBV treatment.

Identifying endogenous suppressors targeting hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) will open new avenues for therapeutic options. Here, circRNome and transcriptome analyses were used to identify circRNAs in human HBV-HCC tissues. The role of circM-TMEFF1 was assessed both in vitro and in vivo. circM-TMEFF1 was inversely related to HBV replication and HCC progression and was identified as inhibiting the proliferation, colony formation, and migration of HCC cells and xenograft growth in a mouse model. HBV, IL-1β, and TNF-α up-regulated circM-TMEFF1 expression via trans-activating transcription factors MAFF and MAFK in HCC cells. circM-TMEFF1 sponged let-7e-5p that predominantly targeted deubiquitylase YOD1. circM-TMEFF1 or YOD1 significantly inhibited HBV replication and reservoir, especially for HBV with cancer-promoting mutations in the X gene. circM-TMEFF1/let-7e-5p/YOD1 axis inhibited STAT3 via YOD1 and NF-κB pathway by stabilizing IκBα. Conclusively, circM-TMEFF1 emerges as the first identified circRNA that inhibits HBV and HCC by inhibiting the NF-κB and STAT3 pathways via the circM-TMEFF1/let-7e-5p/YOD1 axis, making circM-TMEFF1 a promising new candidate for treating HBV-related HCC.

This study focuses on the optimization of Calcicamide A, a marine-derived bisindole natural product, as a novel anti-breast cancer stemness agent targeting the IL-6/STAT3 signaling pathway. We report the first total synthesis of Calcicamide A, which demonstrates a selective inhibitory effect on breast cancer, and design a series of derivatives to explore their structure-activity relationships (SARs). Among these, XQ-26 emerges as a potent inhibitor of breast cancer (BC) stemness, demonstrating significant anti-proliferative effects on BC cell lines. XQ-26 effectively suppresses colony formation, migration, invasion, and tumorsphere formation of BC cells, while reducing the tumor stemness markers CD133+ and CD44+. It also induces apoptosis and G1 phase cell cycle arrest in BC cells. Mechanistically, XQ-26 targets the IL-6/JAK2/STAT3 signaling pathway by downregulating the protein levels of IL-6 receptors (gp130 and gp80), decreasing phosphorylated JAK2 (p-JAK2) and phosphorylated STAT3 (p-STAT3) levels at Tyr705 and Ser727 residues, and inhibiting STAT3 nuclear translocation, thereby regulating the expression of downstream target genes related to cell cycle (Cyclin D1, CDK4) and apoptosis (Bax, Bcl-2, PARP). In vivo, XQ-26 significantly inhibits 4T1 tumor growth with minimal toxicity and enhances the therapeutic efficacy of cisplatin. These findings highlight XQ-26 as a promising anti-breast cancer stemness agent, offering a potential therapeutic strategy for BC treatment.

e16162 Background: Advanced intrahepatic cholangiocarcinoma (ICC) carries a dismal prognosis, with limited second-line options after failure of gemcitabine-based chemotherapy. Adebrelimab (anti-PD-L1 antibody) plus lenvatinib has shown potential in hepatobiliary cancers. This study evaluated the efficacy and safety of this combination in advanced ICC patients with heavy tumor burden and impaired liver function. Methods: This single-arm, open-label, phase II study enrolled patients with histologically confirmed unresectable or metastatic ICC who progressed on or were intolerant to first-line chemotherapy. Patients received adebrelimab (20 mg/kg IV Q3W) and oral lenvatinib (8 mg/day for weight < 60 kg; 12 mg/day for ≥60 kg). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety (CTCAE v5.0). Results: As of January 12, 2026, 28 patients were enrolled (median age, 60.0 years). The cohort represented an exceptionally high-risk population: 18 patients (64.3%) had extrahepatic metastases, 13 (46.4%) had vascular invasion, and 20 (71.4%) were Child-Pugh class B. Furthermore, 24 patients (85.7%) met the "up-to-seven" criteria. After a median follow-up of 8.5 months (95% CI, 4.5 to 12.2), the median OS reached 12.2 months (95% CI, 6.3 to not reached), with a 12-month OS rate of 59.5% (95% CI, 40.9% to 86.5%). The median PFS was 6.3 months (95% CI, 4.0 to 12.4). In the ITT population, the ORR was 7.1% (2 of 28) and the DCR was 53.6% (15 of 28); however, response assessment was confounded by early treatment discontinuation or pending evaluations in 12 patients (42.9%). Treatment-related adverse events (TRAEs) of any grade occurred in 27 patients (96.4%). Grade 3-4 TRAEs were reported in 6 patients (21.4%), most commonly hepatic encephalopathy (3 patients, 10.7%), limb/shoulder pain (2 patients, 7.1%), and hyperbilirubinemia (2 patients, 7.1%). No treatment-related deaths were observed. Conclusions: Adebrelimab combined with lenvatinib demonstrated an unprecedented median OS of 12.2 months in second-line advanced ICC. Importantly, this survival benefit was maintained even in a population predominantly comprised of Child-Pugh class B patients with significant tumor burden. This combination represents a potential breakthrough for this difficult-to-treat population and warrants further validation in a randomized controlled trial. Clinical trial information: ChiCTR2300078869.

While mpox is typically a self-limiting zoonosis, individuals with advanced human immunodeficiency virus type 1 (HIV-1) infection are at increased risk for severe visceral complications and high mortality. We report a fatal case of fulminant mpox pneumonia in a 38-year-old male with advanced HIV-1 Infection and severe immunosuppression (CD4+ T-cell count <100 cells/µL). The patient initially presented with characteristic cutaneous lesions but rapidly progressed to dyspnea and respiratory failure. Serial chest imaging revealed diffuse, solid perivascular nodules and patchy consolidations were highly suggestive of pulmonary malignancy. While initial microbiological cultures and clinical presentation (Day 4) suggested bacterial and fungal superinfections, metagenomic next-generation sequencing (mNGS) of lung tissue biopsy identified an overwhelming burden of mpox virus (MPXV; 260,840 sequence reads), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), confirming direct viral invasion of the pulmonary parenchyma. Despite comprehensive treatment with antibiotics, antifungals, CMV-targeted therapy, and mechanical ventilation (specific anti-orthopoxvirus agents were unavailable), the patient succumbed to progressive respiratory failure on Day 31. This case highlights that mpox can manifest as severe necrotizing pneumonia with tumor-like radiological features in patients with acquired immunodeficiency syndrome (AIDS). It underscores the necessity of early pulmonary imaging and molecular testing in high-risk populations to differentiate mpox pneumonia from malignancy or opportunistic infections.

BACKGROUND:Chronic hepatitis B (CHB) virus infection is the leading cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogs (NAs) effectively suppress HBV replication, but residual HCC risk remains in treated patients, highlighting the need for reliable risk stratification tools. Existing prediction models rely heavily on age and liver function parameters and often overlook hepatitis B surface antigen (HBsAg) quantification, a key marker closely tied to HBV-related HCC, resulting in inadequate clinical predictive accuracy. METHODS:To address this gap, we developed the novel HBsAg-HCC Score using a two-cohort design: retrospective training (1190 NA-treated CHB patients) with Cox regression to identify independent HCC risk factors, followed by validation in an independent prospective cohort (506 patients). Its performance was compared with three established tools (PAGE-B, mPAGE-B, aMAP). RESULTS:Five independent HCC risk factors were identified: higher HBsAg levels, older age, male sex, hypoproteinaemia, and elevated APRI. The HBsAg-HCC Score derived from these factors showed strong predictive power: 3-/5-/7-year AUCs of 0.867/0.872/0.871 in the training cohort (significantly outperforming PAGE-B, mPAGE-B, aMAP) and 0.784/0.780/0.777 in the validation cohort. Internal and external cross-validation confirmed its stability and reliability. CONCLUSIONS:By incorporating HBsAg quantification, a virus-specific marker often missing from conventional models, the HBsAg-HCC Score offers a more comprehensive and accurate approach to HCC risk stratification in NAs-experienced CHB patients, addressing a critical limitation of existing models directly.

IntroductionThe efficacy of oncolytic adenoviruses in colorectal cancer models is constrained by a treatment-induced limitation: the high-dose, repetitive administration required for sustained oncolysis promotes chronic antigen exposure and tumor microenvironmental stress, driving CD8+ T cells into a state of exhaustion.MethodsTo mitigate this, we constructed an oncolytic adenovirus, ADV-PTD4-D3, engineered for intratumoral expression of a peptide inhibitor of CDK4/6. This local strategy aims to retain immunomodulatory potential while minimizing systemic exposure. In syngeneic murine models, ADV-PTD4-D3 demonstrated improved tumor control and the ability to induce robust, antigen-specific immunological memory, with its therapeutic effect being primarily dependent on CD8+ T cells. Notably, it also exhibited potent antitumor activity in a humanized xenograft model and showed no evidence of significant off-target toxicity in immunocompetent hosts.ResultsThe mechanism involves a signaling axis where viral-mediated CDK4/6 inhibition reduces retinoblastoma (Rb) protein phosphorylation. This decrease relieves Rb-mediated sequestration of the NF-kB p65 subunit, allowing p65 nuclear translocation and transcriptional upregulation of the T-cell chemoattractant CCL5, a factor linked to favorable patient prognosis. Thus, ADV-PTD4-D3 promotes a T-cell-inflamed microenvironment by providing a sustained chemotactic signal CCL5 for CD8+ T cell recruitment. Furthermore, this treatment strategy successfully reverses the functional exhaustion of infiltrating CD8+ T cells, thereby addressing two major barriers to effective therapy: inadequate infiltration and functional exhaustion. By modifying the tumor microenvironment in this way, the armed virus addresses two factors that limit T-cell-based immunotherapies: inadequate infiltration and functional exhaustion. Correspondingly, ADV-PTD4-D3 treatment improved the antitumor response to both PD-1 blockade and CAR-T cell therapy in combination studies.DiscussionThese findings suggest that engineering oncolytic viruses to locally modulate pathways involved in T cell exhaustion represents a viable and translatable strategy for enhancing antitumor immunity.

Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-TyrGUA. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-TyrGUA ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.

Obesity is a global health issue. Traditional treatment modalities such as lifestyle modifications, pharmacological interventions, and bariatric surgery often present various limitations. Recently, endoscopic bariatric and metabolic therapies (EBMTs) have emerged as promising minimally invasive approaches for weight management. These therapies reduce gastric volume and energy intake, prolong gastric emptying, and regulate hormones associated with satiety. This study evaluated endoscopic gastric purse-string suturing (EGPSS), a novel endoscopic procedure designed to reduce gastric fundus volume while minimizing associated risks. We assessed its feasibility and efficacy in a porcine model in terms of histological, physiological, and metabolic outcomes. The results suggest that EGPSS offers a viable option for metabolic control.

BACKGROUND:Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I (rtCYE/rtCYEI) mutations in the hepatitis B virus (HBV) reverse-transcriptase (RT) region are associated with tenofovir disoproxil fumarate (TDF) resistance is controversial. AIM:To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection. METHODS:A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled. All patients received nucleoside/nucleotide analogues (NAs) therapy, and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis. RESULTS:The detection rates of a single mutation of rtS106C, rtH126Y, rtD134E, and rtL269I were 8.21%, 3.20%, 2.55% and 61.49% in 23718 genotype C patients, and 1.31%, 1.76%, 0.21%, and 92.33% in 4266 genotype B patients, respectively. The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients, accounting for 0.042% of all patients. These 12 patients had received NA treatments except TDF before testing. Among them, 6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations, and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations. Compared with the wild-type (WT) strain, the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%, and TDF susceptibility reduced by less than 2-fold, but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility. Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain. In the clinic, emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment. CONCLUSION:HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.

Whether patients aged ≤30 years with chronic hepatitis B (CHB) and normal alanine transaminase (ALT) levels (<40 U/L) should receive antiviral therapy is controversial. In this study, we aimed to identify high-risk factors of significant hepatic damage (SHD) and established a scoring system to guide the decision to administer antiviral treatment. Eligible patients who underwent a liver biopsy were retrospectively screened and randomly assigned to either a training or validation set. Hepatic fibrosis (S0-4) and inflammation (G0-4) were assessed using the Scheuer scoring system. The independent risk factors associated with SHD (≥G2/S2) were identified using univariable and multivariable logistic regression analyses, and a new scoring system based on these factors was established. Among the 883 enrolled patients, 548 (62.1 %) were male, and 250 (28.5 %) presented with SHD. ALT, platelet count, HBV DNA, and liver stiffness measurement were identified as independent risk factors. A new scoring model based on these factors, named APLB, was developed. The area under the curve of APLB was 0.731 (95 % confidence interval, 0.695-0.764), which was significantly higher than those of the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) index. An APLB score <6 points ruled out SHD with 80.2 % sensitivity, while scores >12 points diagnosed SHD with 97.5 % specificity. In conclusion, the APLB scoring model demonstrated superior diagnostic performance compared with the APRI and the FIB-4 index, and it has the potential to guide the decision to initiate antiviral therapy in this patient group.

Low-level viremia (LLV) still occurs in some patients with chronic hepatitis B (CHB) after entecavir (ETV) treatment. We aimed to evaluate the effects of LLV on the adverse long-term outcomes. A secondary analysis of a multicenter prospective cohort study, consisting patients who underwent liver biopsy and received entecavir treatment, was conducted. LLV was defined as detectable HBV DNA levels (20-2000 IU/mL) at week 48 after the imitation of ETV treatment, maintained complete virological response (CVR) was defined as HBV DNA <20 IU/mL. The zero time was defined as the date of LLV diagnosis, the primary endpoint was the occurrence of HCC. The time-to-event analyses were performed using log-rank analysis, and multivariable COX regression. The inverse probability of treatment weighting and propensity score matching were used in the sensitivity analyses. In total, 766 patients were enrolled in the final analysis, and LLV was found in 182 patients (23.8 %). Patients with LLV had a significantly higher 7-year cumulative incidence of HCC (18.7 % vs. 8.1 %, p < 0.001) and fibrosis progression rate (17.5 % vs. 8.7 %, p = 0.017) than those with CVR. Multivariate analysis identified LLV as an independent risk factor associated with HCC (adjusted HR: 3.935; 95 % CI: 2.218-6.979, p < 0.001) and fibrosis progression (adjusted OR 5.342; 95 % CI: 1.630-17.480, p = 0.006). A nomogram incorporating LLV, age, PLT and liver cirrhosis was developed and validated for HCC risk prediction, demonstrating excellent performance with a C-index of 0.778. In conclusion, LLV significantly promoted HCC occurrence and fibrosis progression in CHB patients receiving anti-HBV treatment.

This study assessed serum hepatitis B core-related antigen (HBcrAg) and antibodies to hepatitis B core antigen (qAnti-HBc) as noninvasive biomarkers for detecting intrahepatic replication-competent HBV DNA (repDNA) in chronic hepatitis B (CHB) patients who had lost HBsAg. The goal was to identify alternatives to liver biopsy for diagnosing residual HBV activity after HBsAg loss.A novel over-gap droplet digital PCR (ddPCR) assay was developed for sensitive intrahepatic repDNA detection. Over-gap ddPCR detected repDNA in 88.24% (135/153) of patients, which was a significantly greater percentage than traditional nested PCR (75.16%, 115/153; P < 0.01). HBcrAg was positive in 41.83% (64/153) of patients, and repDNA positivity was markedly greater in HBcrAg-positive patients (93.75%, 60/64) than in HBcrAg-negative patients (84.27%, 75/89; P < 0.01). In HBsAg-negative CHB patients, the HBcrAg level was moderately positively correlated with the intrahepatic repDNA level (r = 0.470, P < 0.001), whereas this correlation was not detected in liver cirrhosis patients. For predicting the intrahepatic repDNA status in HBsAg-negative CHB patients, the area under the receiver operating characteristic curve (AUC) was 0.773 for HBcrAg alone and 0.803 for qAnti-HBc alone. Notably, the combination of HBcrAg and qAnti-HBc significantly improved diagnostic accuracy, achieving an AUC of 0.913. The novel over-gap ddPCR assay exhibits superior sensitivity for intrahepatic repDNA detection. Serum HBcrAg, particularly when combined with qAnti-HBc, effectively predicts the intrahepatic repDNA status in HBsAg-negative CHB patients, providing a valuable non-invasive tool to replace liver biopsy for assessing residual HBV replication.